OVERALL ABSTRACT The common occurrence, marked debilitation and subsequent lethality of prostate cancer (PCa) skeletal metastases has made it a major health concern. In the first fourteen years of this program, we have addressed this important issue, resulting in a major impact on the field of skeletal metastasis research, including promoting concepts such as crosstalk between tumor and bone and the importance of therapeutically targeting the microenvironment, in addition to tumor. This program has resulted in over 220-grant-related publications and set groundwork for several clinical trials. In the current competitive renewal, we further attack this problem by combining leading expertise in PCa research and bone biology. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that fosters the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to alter the bone microenvironment and render it fertile for tumor growth and chemotherapeutic resistance. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel finding that chemotherapy induces fusion of PCa cells to form multinuclear polyploid giant cancer cells (PGCCs) that confer chemoresistance in the bone microenvironment; Project 2 examines the exciting idea that abscisic acid (ABA) induces PCa cells to adopt a phenotype capable of existing in a dormant and chemoresistant state, with the capacity for long-term survival and potential to develop into overt bone metastases; Project 3 explores the surprising role that osteocytes (OCys) play in promoting PCa bone metastasis through activation of a novel growth differentiation factor-15 (GDF15) receptor, GDFN family receptor alpha-like precursor (GFRAL), that subsequently promotes PCa metastatic invasion and growth; Project 4 investigates the novel hypothesis that macrophage efferocytosis (engulfment) of apoptotic PCa cells induces immunosuppressive signaling in the bone microenvironment that subsequently enhances metastatic growth. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation of progress, advisory board activities, facilitate interactions among the projects and provide biostatistical support; Core B (Animal) will provide mouse models and imaging and assistance with their use and Core C (Bone) will provide expertise with bone histology processing, interpretation, and procurement of human blood and bone marrow samples. This combination of investigators, projects and cores provides a highly synergistic Program that is greater than the sum of its parts and will continue to provide cutting-edge research and leadership in the field of PCa skeletal metastases.